Chronic non-healing wounds persist as a US health care. Type II diabetes mellitus with characteristic hyperlipidemia and hyperglycemia is common in overweight Americans and is a major risk factor for neurovascular complications. Multiple analyses from the Diabetes Control and Complications Trial demonstrate that patients treated with standard insulin therapy exhibit sustained inflammatory responses and develop vascular complications in spite of subsequent intensive insulin intervention. These findings have generated the widely accepted 'metabolic memory'theory that transient hyperglycemia involves epigenetic modifications that alter gene expression. Epigenetic modifications have been increasingly correlated with human diseases and such associations are essential for understanding the pathophysiology of chronic diabetic wounds. Our hypothesis for this new project is that 1) elevated levels of glucose and fatty acids, even transiently, alter paracrine interactions between dermal microvascular endothelial cells and neural progenitor cells in a sustained manner and 2) anti-oxidants abrogate the dysfunctional responses to glucose and fatty acids. We will test our hypothesis by addressing the following three Specific Aims: 1. to determine whether transient exposure to elevated glucose and fatty acid levels causes a metabolic memory that induces sustained changes in microvascular endothelial and neural progenitor cell responses to injury. We determine whether dermal microvascular endothelial cells and neural progenitor cells have impaired responses to injury after transient exposure to glucose and fatty acids. Based on published data on other cell types, we expect that transient glucose and fatty acid exposure has sustained epigenetic effects on these cells. 2. To determine whether antioxidants abrogate the effects of elevated glucose and fatty acids on microvascular endothelial cells and nerve progenitor cells. Our proposal to evaluate whether antioxidants vitamins E and C reverse effects of glucose and fatty acids on endothelial cell and neural progenitor cell responses will determine whether detrimental effects of glucose and fatty acids are reversible or preventable. 3. To determine whether a transient high fat, high glucose diet affects wound healing in diabetic and non-diabetic mice. We believe that supplementing the diet with the antioxidants vitamins E and C will abrogate the adverse dietary effects and will prevent epigenetic effects. PUBLIC HEALTH RELEVANCE: In this new project, we propose that the novel concept that transient exposure to elevated levels of glucose and fatty acids induces oxidative stress that causes sustained impairment in neural progenitor cell and dermal microvascular endothelial cell responses to cutaneous injury due to a phenomenon known as 'metabolic memory.'Furthermore, we propose that vitamin E and vitamin C, two antioxidants abrogate the epigenetic effect of the environmental perturbation and minimize the sustained effects.